This application concerns the pathological accumulation of Abeta oligomers (ADDLs) in brains and CSF of individuals at various stages of Alzheimer's disease (AD). This disease strikes 10 percent of individuals over 65, inflicting painful emotional burden to families and a cost to the country of more than $100 billion annually. Despite its serious impact, our ability to contend with AD suffers from imprecise diagnostics and inadequate therapeutics. The current project addresses these problems by investigating the clinical properties of ADDLs, which we identified as metastable neurotoxins that accumulate in AD brain and CSF. It now appears likely that ADDLs play a significant role in the neuronal dysfunction and damage responsible for AD's progressively catastrophic dementia (Health &Human Services 2004-2005 Progress Report on Alzheimer's Disease). To advance our understating of this pathogenic role, we propose to test the hypothesis that an attack on synapses by ADDLs initiates tau hyperphosphorylation, oxidative damage and synapse deterioration, thus providing a comprehensive mechanism for memory failure and the major facets of AD neuropathology. This hypothesis, which is strongly supported by findings from cell biology and neuropathology, will be investigated primarily using human ADDLs and CNS samples in order to directly establish clinical relevance. We also propose to investigate why AD-affected brain is unable to remove ADDLs, following up on newly reported neuropathological data suggesting a failure of glial clearance mechanisms. Building on recent results, our seven aims are to: (i) Validate that ADDLs in CSF/plasma provide a reliable AD biomarker;(ii) Verify that the earliest preclinical sign of AD is ADDL accumulation around individual neurons;(iii) Test the prediction that neurons surrounded by ADDLs develop AD pathology;(iv) Verify that perineuronal deposits of ADDLs are due to ADDL attachment to synapses;(v) Identify the pathogenically significant oligomeric species (putatively 12mers) and obtain new monoclonal antibodies that specifically target disease-relevant oligomers;(vi) Test the predicted role of synaptic membrane proteins in the mechanism by which ADDLS attack only particular neurons;and, (vii) Confirm the novel ADDL-related pathology discovered in astrocytes, testing its relevance to failed ADDL clearance mechanisms in disease onset and progression. Important technical innovations include ultrasensitive nanotechnology-based ADDL assays, monoclonal antibodies specific for ADDLs in solution, and a series of physicochemical methods capable of characterizing oligomer size in dilute aqueous solutions without the use of SDS or other harsh chemicals. Results are expected to provide important advances needed to validate and optimize ADDLs as major targets for Alzheimer's diagnostics and disease-modifying therapeutics. PUBLIC HEALTH RELEVANCE: This application concerns the role of Abeta oligomers (ADDLs) in Alzheimer's disease, focusing on human samples to establish direct clinical and pathological relevance. Results obtained with human ADDLs and tissue will help answer important questions central to ADDL involvement in pathogenesis and substantiate the targeting of ADDLs for future diagnostics and therapeutics.